ACT against multiple myeloma

Adoptive T cell therapy (ACT) has had some success in treating certain types of cancer; however, widespread use is limited in part by the lack of tumor-specific targets. Tumor-infiltrating T cells may overcome this limitation for solid tumors. Noonan et al. now show in a phase 1 clinical trial that bone marrow can be a source of ACT for hematologic malignancies such as multiple myeloma. Marrow-infiltrating lymphocytes (MILs) demonstrated myeloma-specific immunity in the bone marrow up to 1 year after ACT, and a significant increase was observed in progression-free survival. If these results can be replicated in larger studies, MILs may represent a source for ACT for hematologic malignancies and bone marrow–infiltrating solid tumors.

Abstract

Successful adoptive T cell therapy (ACT) requires the ability to activate tumor-specific T cells with the ability to traffic to the tumor site and effectively kill their target as well as persist over time. We hypothesized that ACT using marrow-infiltrating lymphocytes (MILs) in multiple myeloma (MM) could impart greater antitumor immunity in that they were obtained from the tumor microenvironment. We describe the results from the first clinical trial using MILs in MM. Twenty-five patients with either newly diagnosed or relapsed disease had their MILs harvested, activated and expanded, and subsequently infused on the third day after myeloablative therapy. Cells were obtained and adequately expanded in all patients with anti-CD3/CD28 beads plus interleukin-2, and a median of 9.5 × 108 MILs were infused. Factors indicative of response to MIL ACT included (i) the presence of measurable myeloma-specific activity of the ex vivo expanded product, (ii) low endogenous bone marrow T cell interferon-γ production at baseline, (iii) a CD8+ central memory phenotype at baseline, and (iv) the generation and persistence of myeloma-specific immunity in the bone marrow at 1 year after ACT. Achieving at least a 90% reduction in disease burden significantly increased the progression-free survival (25.1 months versus 11.8 months; P = 0.01). This study demonstrates the feasibility and efficacy of MILs as a form of ACT with applicability across many hematologic malignancies and possibly solid tumors infiltrating the bone marrow.